This guidance applies to devices that are labeled as sterile through microbial inactivation. It distinguishes established sterilization methods and those that are novel. That is FDA has established a bifurcated universe of “established” versus “novel.” It is unlikely, though, that all 510(k)s will neatly fall into this scheme. This scheme is also different from the original scheme proposed by FDA in the draft guidance with more methods falling under the “established” category than the draft, which proposed a three-tier system of “traditional,” “non-traditional,” and “novel non-traditional.”

Established methods are those for which there is an FDA-recognized standard and are well-accepted, for example dry heat, EO, steam, and radiation. Established methods are also those for which there is no FDA-recognized standard, but there is “published information on development, validation, and routine control available” and/or FDA has previously reviewed and accepted the sterilization method as being acceptable (e.g., through clearance of a 510(k) for a device sterilized with such a method). These established methods include, for example, hydrogen peroxide, ozone, and flexible bag systems.

On the other hand, novel methods are “newly developed methods for which there exists little or no published information, no history of comprehensive FDA evaluation” and no FDA-recognized consensus standard. Novel methods include, among other things, brand new sterilization methods, changes to parameters of established methods, and combinations of established sterilants which FDA has not previously reviewed or cleared. It is worth noting that the guidance states that a method is novel if “parameters of an FDA-cleared sterilizer have been altered.” The guidance does not address how significant the alterations must be in order to be considered novel. As a result, on its face, it appears that any change to an FDA-cleared sterilizer’s parameters would result in a “novel” sterilization method.

The guidance indicates that FDA intends to inspect device manufacturing facilities that employ novel sterilization methods prior to clearing 510(k)s for such devices. The draft guidance also indicated that pre-clearance inspections would be required for novel sterilization methods. The draft guidance also stated that FDA would perform priority post-clearance inspections of device manufacturing facilities utilizing sterilization methods for which there is no FDA-recognized standard, but there is published information on its validation and FDA has previously reviewed and accepted the sterilization method as being acceptable (previously referred to as non-traditional methods, and now encompassed within the definition of “established” methods). The statement regarding post-clearance inspections has been omitted from the final guidance, and it should be noted that it is unclear what FDA meant by a “priority” inspection in this context. It is not to say, however, that FDA will not still consider performing such post-clearance inspections.

With regard to pre-clearance inspections, the guidance does not indicate how FDA will ensure that such an inspection takes place within the Federal Food, Drug, and Cosmetic Act mandated 90 day review time frame for 510(k)s. Nor does the guidance indicate how FDA will handle inspectional findings that result from such pre-clearance inspections, what effect those findings will have on a pending 510(k) or its review timing, or what the inspectional criteria will be. Historically, FDA has not considered QSR compliance as part of making a substantial equivalence determination, and its ability to use QSR compliance in making an initial classification decision is limited by statute. FDC Act § 513(f)(5).

Moreover, the guidance creates a new standard for sterilization information required in 510(k)s, and although the guidance is nonbinding, failure to comply will likely result in a finding of not substantially equivalent. For devices sterilized by established methods, the guidance indicates that the sterilization information from the current 510(k) Refuse to Accept policy (a copy of the current requirements for sterile devices is at the end of this post) and the CDRH premarket coversheet (i.e., the sterilization facility) should be submitted in a 510(k) plus the following information:

A description of the sterilization chamber (e.g., rigid or fixed);

If the sterilization method is not the subject of an FDA-recognized consensus standard, but the sterilizer or sterilization method has been cleared by FDA:

the 510(k) number,

the make and model of the sterilizer, and

whether the proposed sterilization cycle is identical to a cleared cycle or has been altered (note: if it has been altered then it would be considered a novel method under the guidance);

If the method has not been previously cleared by FDA, but there is “published information on development, validation, and routine control available” it should be stated;

The radiation dose, if the device is sterilized by radiation;

If the sterilization method is not the subject of an FDA-recognized consensus standard, “a comprehensive description of the process and the complete validation protocol;” and

A description of not only the packaging, but also how it will “maintain the device’s sterility, and a description of the package test methods, but not package test data.”

For novel methods, the above information must be provided along with the following additional information:

“A comprehensive description of the sterilization process;

The method used to validate the sterilization cycle (e.g., the half-cycle method);

The validation protocol; and

The sterilization validation data. The submission should also identify any applicable published scientific literature.” Note: the requirement to provide the sterilization validation data is in direct contradiction of the current version of the 510(k) RTA, which expressly states that “the sterilization validation report is not required.” We think it would be too cute for FDA to say that asking for the data rather than the report was not a contradiction.

The guidance also provides additional information regarding the information needed to support a “non-pyrogenic” claim and the types of devices for which pyrogenicity data should be provided. These sterilization and pyrogenicity requirements have been modified in the final guidance compared to the draft guidance.

The draft guidance also set out detailed steps for how the reviewers should route sterilization information during a 510(k) reviewing, including, requesting inspections and involving the Infection Control Devices Branch (ICDB) in its review of novel sterilization methods. This detailed routing information and references to the ICDB’s involvement have all been omitted from the final guidance. It is possible that the review team will follow the draft process internally, and it was simply omitted from the public-facing final guidance.

Although the guidance is neither binding nor set out in the 510(k) RTA, we expect that FDA will begin enforcing these requirements sooner rather than later, even if not officially. As a result, manufacturers will want to ensure that they are familiar with these new sterilization requirements prior to submitting a 510(k) to FDA.